Lymphangioleiomyomatosis (LAM) is a rare disorder that affects women at their prime of their lives by gradually destroying the lungs leading to incapacitation. Lung transplant is the only known effective therapy. Although new drug treatment may be on the horizon, many aspects about this disease remain an enigma. Here, we will investigate a new paradigm that takes into account some of the unique features of LAM including the cellular heterogeneity, their potential to metastasize, and the influence of sex hormones. We also hope to develop an animal model of LAM that will serve as a useful tool for further investigations into disease pathogenesis and therapeutics. PUBLIC HEALTH RELEVANCE: Lymphangioleiomyomatosis (LAM) is a potentially fatal but uncommon disease that predominantly affects the lungs of females during their reproductive age. No curative therapy is available, and the underlying pathogenesis remains poorly understood. In this proposal, we will examine the role of the TSC2 gene and sex hormones in a novel 'two-hit'model of LAM development that may provide new strategies towards treatment of this disease.